Hydroxyalkyl-substituted-amino-quinolines

ABSTRACT

Disclosed are compounds of the class of quinolines substituted at the 2-, 3- or 4-position by an amino function bearing a hydroxyalkyl nitrate moiety, e.g. 4-(2-hydroxyethylpiperazino)-quinoline nitrate. The compounds have various pharmacological activities in animals and are useful, for example, as hypotensive and anti-anginal agents. Also disclosed are the corresponding hydroxy intermediates which are useful in preparation of the nitrates and also as hypotensive and anti-anginal agents.

This application is a division of application Ser. No. 504,427, filedSept. 9, 1974, now U.S. Pat. No. 3,957,791, which is a division ofapplication Ser. No. 291,833, filed Sept. 25, 1972, now U.S. Pat. No.3,856,796, which in turn is a continuation-in-part of application Ser.No. 245,308, filed Apr. 19, 1972 which in turn is a continuation-in-partof application Ser. No. 127,376, filed Mar. 23, 1971, now bothabandoned.

This invention relates to quinoline derivatives, and more particularlyto pharmacologically active quinolines which are substituted at the 2-,3- or 4- position by an amino function bearing a hydroxyalkyl nitratemoiety. The invention further relates to corresponding hydroxyalkylsubstituted amino-quinolines useful as intermediates in preparation ofsaid nitrates and also possessing pharmacological activity. Theinvention also relates to pharmaceutical methods and compositionsutilizing said compounds.

The compounds of the invention may be represented by the structuralformula I: ##STR1## wherein R is from the group of

A. --CH₂ (--CH₂)_(n) --ONO₂ ##STR2## d. --CH₂ (--CH₂)_(z) --N[CH₂(--CH₂)_(y) --ONO₂ ]₂

R₁ is from the group of

E. --CH₂ (--CH₂)_(n) -- ONO₂ when R is a) as above defined,

F. hydrogen, and

G. lower alkyl of 1 to 4 carbon atoms,

R' is --(CH₂ --) _(x) CH₃ or --(CH₂)_(y) ONO₂,

R^(o) is hydrogen, --(CH₂ --)_(m) CH₃ or --(CH₂ --)_(y) ONO₂, providedthat one R^(o) (and only one) is other than hydrogen, that the sum of nand m does not exceed 7 and that the sum of n and y does not exceed 8,or

R and R₁ together with the 4- amino nitrogen attached to the quinolinering form ##STR3## n is 1 to 7, preferably 3 to 5, M IS 0 TO 4,

x is 0 or 1,

y is 1 to 4,

z is 1 to 4, and

each of Y, Y', Y" and Y'" is hydrogen, halo of atomic weight of from 18to 80, i.e., fluoro, chloro or bromo, lower alkoxy of 1 to 3 carbonatoms, e.g, methoxy or lower alkyl of 1 to 3 carbon atoms, e.g., methyl,or Y and Y' together form methylenedioxy; provided that at least 2 of Y,Y', Y" and Y'" are hydrogen and further provided that when one of Y, Y',Y" and Y'" is halo then the others are hydrogen, or a 1-lower alkyl(C₁-C₃)iodide, the 1-trifluoromethyl iodide or the 1-(ω,ω,ω-trifluoro)ethyliodide thereof.

A preferred method for preparation of the compounds of formula Iinvolves in a Step A reaction the nitration of the corresponding hydroxycompound of formula II: ##STR4## or a corresponding iodide thereof,wherein R₂ and R₃ are the non-nitrate bearing hydroxyalkyl substituentscorresponding to R and R₁, respectively, i.e.:

R₂ is from the group of:

a. --CH₂ (--CH₂)_(n) --OH ##STR5## d. --CH₂ (--CH₂)_(z) --N[--CH₂(--CH₂)_(y) --OH]₂

R₃ is from the group of:

e. --CH₂ (--CH₂)_(n) --OH when R₂ is a) as above defined,

f. hydrogen,

g. lower alkyl of 1 to 4 carbon atoms,

R_(a) ' is --(CH₂)_(x) CH₃ or --(CH₂)_(y) OH, R_(a) ^(o) is hydrogen,--(CH₂ --)_(m) CH₃ or --(CH₂ --)_(y) OH, provided that one R_(a) ^(o) isother than hydrogen, that the sum of n and m does not exceed 7 and thatthe sum of n and y does not exceed 8, or

R₂ and R₃ together with the 4- amino nitrogen attached to the quinolinering form ##STR6## n, m, y and z and Y, Y', Y" and Y'" are as defined.

The preparation of compounds I by step A involves a nitration reactionwhich may be carried out in a manner known per se for nitratinghydroxyalkyl groups. A preferred method of conducting the nitrationinvolves the reaction of a compound II with nitric acid in presence of acarboxylic acid anhydride which is preferably of from 3 to 8 carbonatoms, more preferably acetic acid anhydride. The reaction may besuitably carried out in an organic solvent medium at temperatures in therange of from minus 70° to plus 50° C., preferably minus 5° to plus 20°C. The solvent medium for the reaction is preferably provided byemploying a lower aliphatic carboxylic acid, e.g., acetic acid, althoughother well known organic solvents may be employed or the reaction may becarried out employing an excess of the carboxylic acid anhydride. Theproduct compound I may be isolated from the reaction mixture of Step Aby working up by established procedures.

A preferred method for preparation of compounds II involves a step Breaction of a corresponding haloquinazoline of formula III: ##STR7## ora corresponding iodide thereof, wherein Y, Y', Y" and Y'" are as definedand X is halo from the group of chloro or bromo, preferably chloro witha compound of formula IV: ##STR8## wherein R₂ and R₃ are as defined.

The reaction of Step B is of known type and may be carried out in aconventional manner by subjecting a compound III to reaction with thecompound IV at elevated temperatures which may be suitably in the rangeof 30° to 180° C., preferbly 60° to 160° C. The reaction may be suitablycarried out in an inert organic solvent which may be any of several ofthe well-known conventional solvents such as dioxane. A generallypreferred solvent is isopropanol. Alternately, the reaction may beinitiated and/or carried out in the inert liquid medium provided byemploying an excess of compound IV when the compound is liquid at thereaction temperature or by fusion of solid reactants. An acid bindingagent such as sodium carbonate may be also employed to advantage in thereaction, if desired. The reaction product compound II may be isolatedfrom the reaction mixture of Step B by established procedures.

However, the preferred procedures for the preparation of the iodides ofthe compounds of the formulae I and II involves reacting thecorresponding compound of the formulae I and II, respectively, with theiodides at temperatures in the range of from 20° to 100° C. The reactionmay be carried out in inert organic solvents of conventional type but itis generally preferred to use an excess of the iodide as the solesolvent and conduct the reaction at the reflux temperature of thesystem.

The compounds of formula III and IV are either known or may be preparedfrom known materials by established procedures.

The compounds of the formulae I and II may be produced in the form ofacid addition salts and the pharmaceutically acceptable acid additionsalts are also included within the scope of the invention. Such saltsinclude the acid addition salts, e.g., the methane sulfonate,hydronitrate, hydrosulfonate, fumarate, hydrochloride and maleate. Suchsalts may then be readily converted to the free bases by conventionalprocedures. In preparing the free bases from the acid addition salt, itis also convenient to employ a buffer system, e.g., a system comprisinga 1:1 molar mixture of acetic acid and sodium acetate, followed byworking up by conventional procedures. The free bases may be readilyconverted into the hydronitrate and other acid addition salts byestablished procedures.

The compounds of the formula I and II (including their iodides) andtheir pharmaceutically acceptable acid addition salts, are usefulbecause they possess pharmacological activity in animals. In particular,the compounds of the formulae I and II are useful as agents for thelowering of blood pressure, e.g., as hypotensive agents, as indicated onintravenous administration to the anesthetized dog in the CannulatedBlood Vessel Test. The compounds of formulae I and II are also useful asantianginal agents as indicated by effecting coronary dilation in theanesthetized dog on intravenous administration and measurement of bloodflow through the anterior descending branch of the left coronary artery.

The compounds of formulae I and II (including their iodides) are furtheruseful as anti-arrhythmic agents, as indicated by polygraph recordingson intravenous administration to the anesthetized dog given Oubain untilthe appearance of constantly occurring ventricular ectopic beats andthen the test compound every two minutes until the arrhythmia reverts tosinus rhythm.

For the above uses, the compounds of the formulae I and II may becombined with a pharmaceutically acceptable carrier, and such otherconventional adjuvants as may be necessary, and administered orally insuch forms as tablets, capsules, elixirs, suspensions and the like orparenterally in the form of an injectable solution or suspension. Forthe above-mentioned uses, the dosage administered will, of course, varydepending upon the compounds used, the therapy desired and the mode ofadministration. However, for use as agents for the lowering of bloodpressure, e.g. as hypotensive agents, and for use as anti-arrhythmicagents, satisfactory results in general are obtained with the compoundsof the formula I and II when administered at a daily dosage of fromabout 0.2 milligrams to about 100 milligrams per kilogram of bodyweight, preferably given in divided doses 2 to 4 times a day, or insustained release form. For most larger mammals, the administration offrom about 16 milligrams to about 500 milligrams of the compond per dayprovides satisfactory results and dosage forms suitable for internaladministration comprise from about 4 milligrams to about 250 milligramsof the compound in admixture with a solid or liquid pharmaceuticalcarrier or diluent.

As anti-anginal agents, satisfactory results may be obtained with thecompounds of the formulae I and II when administered at a daily dosageof from 0.2 to 100 milligrams per kilogram of body weight, given asrequired or in divided doses or in sustained release form. For mostlarger mammals, a dosage of from 16 to 500 milligrams, pro re nata,provides satisfactory results. As anti-anginal agents, the compounds arepreferably administered orally and used to prophylactically prevent orminimize angina attacks at a daily dosage of 16 to 500 milligrams, or individed doses of from 4 to 240 milligrams. The preferred anti-anginalcompounds are those of the formula I.

Various of the compounds of the invention as represented by thecompounds of Examples 4z-1), 4z-9) and 3a) hereinafter also possessperipheral vasodilatory activity as indicated in dogs by the cannulatedblood vessel test following intravenous administration, and aretherefore also indicated for use as peripheral vasodilators. Theindicated suitable modes of administration and daily dosage are the sameas for the indicated hypotensive use, above.

The compounds of formula II (including their iodides) are also useful asanti-obesity agents as indicated by glucose transport tests carried outon male Wistar rats which are dosed orally with 10-150 milligrams perkilogram of body weight of the test compound after at least 20 hours offasting. One hour after receiving the drug each animal is sacrificed andthe upper small intestine is removed and washed with glucose-saline. A 5cm. section of the intestine is everted so that the mucosal surface ison the outside. One end of the segment is tied off and the center of thesac so formed is filled with oxygen saturated Kreb's bicarbonate buffer.The other end is then closed and the sac is incubated in 10 ml. ofoxygen saturated bicarbonate buffer for 60 minutes at 37° C. Both theoutside and inside solutions contain initially 0.3% of glucose. At theend of the incubation time, the glucose content of the outer (mucosal)and the inner (serosal) solution is determined using the standardAutoanalyzer procedure. Similar tests are run simultaneously withcontrol animals. The percent inhibition of glucose transport caused bythe drug is calculated from the formula: ##EQU1## where I = percentinhibition;

S_(t) = glucose concentration (mg.%) of serosal fluid at the end of anexperiment in the drug-treated animal;

S_(c) = glucose concentration (mg.%) of serosal fluid at the end of anexperiment in the control animal;

M_(t) = glucose concentration (mg.%) of mucosal fluid at the end of anexperiment in the drug-treated animal; and

M_(c) = glucose concentration (mg.%) of mucosal fluid at the end of anexperiment in the control animal.

The effective dosage of active ingredient employed for the treatment ofobesity will vary depending on the particular compound employed and theseverity of the condition being treated. However, in general,satisfactory results in the treatment of obesity are obtained when thecompounds II are administered at a daily dosage of from about 0.3milligrams to about 150 milligrams per kilogram of animal body weight,preferably given in divided doses two to four times a day, or insustained release form. For most large mammals, the total daily dosageis from about 30 to 1000 milligrams. Dosage forms suitable for internaluse comprise from about 10 to about 500 milligrams of the activecompound in intimate admixture with a solid or liquid pharmaceuticallyacceptable carrier or diluent.

The preferred anti-obesity agents of the formula II are those in whichR₂ is a), b), c) and d) as defined above with respect to compounds II,more preferably in other than iodide form with R₃ being hydrogen andwith the --NR₂ R₃ moiety being at the 4-position. More particularlypreferred as anti-obesity agents among R₂ being a), b), c) and d) arethose in which R₂ is d), usually with R₃ being hydrogen and in otherthan iodide form, for example, the compound of Example 4(s) hereinafter.

For the above usages, oral administration with carriers may take placein such conventional forms as tablets, dispersible powders, granules,capsules, syrups and elixirs. Such compositions may be preparedaccording to any method known in the art for the manufacture ofpharmaceutical compositions, and such compositions may contain one ormore conventional adjuvants, such as sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide anelegant and palatable preparation. Tablets may contain the activeingredient in admixture with conventional pharmaceutical excipients,i.e., inert diluents such as calcium phosphate, calcium sulphatedihydrate, lactose and talc, granulating and disintegrating agents,e.g., starch and alginic acid, binding agents, e.g., starch, gelatin,polyvinyl pyrrolidone and acacia, and lubricating agents, e.g.,magnesium stearate, stearic acid and talc. The tablets may be uncoatedor coated by known techniques to delay disintegration and adsorption inthe gastro-intestinal tract and thereby provide a sustained action overa longer period. Similarly, suspensions, syrups and elixirs may containthe active ingredient in admixture with any of the conventionalexcipients utilized for the preparation of such compositions, e.g.,suspending agents (methylcellulose, tragacanth and sodium alginate),wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylenesorbitan mono-oleate) and preservatives (ethyl-p-hydroxybenzoate).Capsules may contain the active ingredient alone or admixed with aninert solid diluent, e.g., calcium carbonate, calcium phosphate andkaolin.

A representative formulation is a tablet for administration orally twoto four times a day to prevent or lessen the severity of angina attacksand prepared by conventional tabletting techniques to contain thefollowing ingredients:

    ______________________________________                                        Ingredients               Weight (mg.)                                        ______________________________________                                        Compound of the formula I, e.g.                                               4-(5-hydroxypentyl)amino-7-methoxy-                                           quinoline nitrate maleate 50                                                  Tragacanth                10                                                  Corn starch               25                                                  Lactose                   197.5                                               Talcum                    15                                                  Magnesium stearate        2.5                                                 ______________________________________                                    

A particularly preferred compound for the treatment of angina and/orarrhythmia is 1-methyl-4-(5-hydroxypentyl)amino-8-methoxyquinolinenitrate iodide and tablets containing 30 milligrams (instead of 50milligrams) thereof may be formulated as given above for administrationtwo to four times a day for use in such treatments.

In general, the compositions of the invention adapted for either oral orparenteral administration may contain 1% to 90% by weight of the activeingredient in combination with the inert carrier, more usually 3% to40%.

The following examples are given for the purpose of illustration only.

EXAMPLE 1 2-[3-Bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitratedihydrochloride ##STR9## Step A: Preparation of2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.

A mixture of 5.05 g. of 2-chloroquinoline, 5.5 g. ofbis(2-hydroxyethyl)aminopropylamine and 3.0 g. of sodium carbonate isheated in 20 ml. of refluxing isopropanol for 24 hours. The reactionmixture is then filtered, solvent removed in vacuo and the residuechromatographed over silica gel to obtain an oil of2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.

Step B: Preparation of2-[3-bis(2-hydroxyethyl)aminopropyl]aminoquinoline dinitratedihydrochloride.

A solution of 5.0 g. of2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline in 5.0 g. of glacialacetic acid is added slowly to a stirred cooled (-5° C.) mixture of 15.0ml. of acetic anhydride and 5.0 ml. of 90% nitric acid. Stirring iscontinued for 20 minutes after addition and 500 ml. of diethyl etheradded to obtain an oil which is added to an excess of cooled (0° C.)aqueous ammonia solution. The resulting mixture is extracted with ethylacetate, the organic phase dried and concentrated in vacuo to obtain anoil which is treated with a slight excess of hydrogen chloride inethanol. Addition of diethyl ether yields a solid which isrecrystallized from methanol/diethyl ether to obtain2-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitratedihydrochloride, m.p. 112° C. (decomp.)

EXAMPLE 3

Following the procedure of Example 1, the following compounds arepepared:

a. 2-[4-(2-hydroxyethyl)-1-piperazino]-quinoline.

b. 2-[4-(2-hydroxyethyl)-1-piperazino]-quinoline nitratedihydrochloride, m.p. 263° C. (decomp.).

c. 2-(5-hydroxypentyl)amino-6,7-dimethoxy-quinoline, m.p. 127°-128° C.

d. 2-(5-hydroxypentyl)amino-6,7-dimethoxy-quinoline nitrate fumarate,m.p. 150°-152° C.

e. 2-(2,3-dihydroxypropyl)amino-quinoline.

f. 2-(2,3-dihydroxypropyl)amino-quinoline dinitrate maleate, m.p. 124°C. 124° C. (decomp.).

g. 2-(5-hydroxypentyl)amino-quinoline.

h. 2-(5-hydroxypentyl)amino-quinoline nitrate hydrochloride, m.p.118.5°-120° C.

i. 2-[4-(2-hydroxyethyl)-1-piperazino]-6,7-dimethoxyquinoline, m.p.176°-177° C.

j. 2-[4-(2-hydroxy)-1-piperazino]-6,7-dimethoxy-quinoline nitratedihydrochloride, m.p. 223°-226° C. (decomp.).

EXAMPLE 3 4-[3-Bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitratedihydrochloride. ##STR10## Step A: Preparation of4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.

A mixture of 5.0 g. of 4-chloroquinoline, 7.2 g. ofbis(2-hydroxyethyl)aminopropylamine, 3.0 g. of sodium carbonate and 25ml. of isopropanol is heated in a pressure vessel at 150° C. for 17hours. The resulting mixture is diluted with chloroform, filtered andpurified by filtering over silica gel to obtain an oil of4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.

Step B: Preparation of4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitratedihydrochloride

A solution of 5.0 g. of4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline in 5.0 g. of glacialacetic acid is added slowly to a mixture of 15 ml. of acetic anhydrideand 5.0 ml. of 90% nitric acid with stirring at minus 5° C. Theresulting mixture is allowed to warm to plus 5° C. and after standingfor an additional 5 minutes it is treated with an excess of ice-coldaqueous ammonia solution and then extracted with methylene chloride toobtain an amber oil which is dissolved in 5.0 ml. of ethanol and treatedwith a slight excess of hydrogen chloride in ethanol. Addition ofdiethyl ether yields a solid which is recrystallized frommethanol/diethyl ether to obtain4-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitratedihydrochloride, m.p. 125° C. (decomp.).

EXAMPLE 4

Following the procedure of Example 3 the following compounds areprepared:

a. 4-(4-(2-hydroxyethyl)-1-piperazino]-quinoline.

b. 4-[4-(2-hydroxyethyl)-1-piperazino]-quinoline nitrate dihydronitrate,m.p. 145° C. (decomp.).

c. 4-(5-hydroxypentyl)amino-6,7-dimethoxy-quinoline maleate, m.p.146°-147° C.

d. 4-(5-hydroxypentyl)amino-6,7dimethoxy-quinoline nitratehydrochloride.

e. 4-(2,3-dihydroxypropyl)amino-quinoline.

f. 4-(2,3-dihydroxypropyl)amino-quinoline dinitrate hydrochloride, m.p.163° C.

g. 4-[4-(2-hydroxyethyl)-1-piperazino]-6,7-dimethoxy-quinoline.

h. 4-[4-(2-hydroxyethyl-1-piperazino]-6,7-dimethoxyquinoline nitratedimaleate, m.p. 134°-135° C. (decomp.).

i. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-6,7-dimethoxy-quinoline.

j. 4-[3-bis(2-hydroxyethyl)aminopropyl]-6,7-dimethoxyquinoline dinitrate(as an oil), N.M.R. OCH₃ singletδ 4.00,4.05 p.p.m., --CH₂ --ONO₂ tripletδ 4.55 p.p.m., --NH broad singlet δ 4.62 p.p.m.

k. 2-(5-hydroxypentyl)amino-6-methoxy-quinoline, m.p. 111°-113.5° C.

l. 2-(5-hydroxypentyl)amino-6-methoxy-quinoline nitrate, maleate form,m.p. 123.5° - 124.5° C.

m. 2-[4 (2-hydroxyethyl)-1-piperazino]-6-methoxy-quinoline, m.p.126°-127° C.

n. 2-[4-(2-hydroxyethyl)-1-piperazino]-6-methoxy-quinoline nitrate,maleate form, m.p. 131°-132° C. (decomp.).

o. 2-[3-bis(hydroxyethyl)aminopropyl]amino-6-methoxy-quinoline, m.p.97°-98.5° C.

p. 2-[3-bis(2-hydroxyethyl)aminopropyl]amino-6-methoxy-quinolinedinitrate, dihydronitrate form, m.p. 124°-125° C. (decomp.).

q. 4-(5-hydroxypentyl)amino-8-methoxy-quinoline, m.p. 138°-140° C.

r. 4-(5-hydroxypentyl)amino-8-methpoxy-quinoline nitrate, hydronitrateform, m.p. 149° C. (decomp.).

s. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-8-methoxy-quinoline, m.p.141°-143° C.

t. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-8-methoxy-quinolinedinitrate difumarate form, m.p. 109°-110° C. (decomp.).

u. 2-[3-bis(2-hydroxyethyl)aminopropyl]amino-6,7-dimethoxy-quinoline,m.p. 88°-90° C.

v. 2-[3-bis(2-hydroxyethyl)aminopropyl]amino-6,7-dimethoxy-quinolinedinitrate fumarate form, m.p. 128°-130° C. (decomp.).

w. 2-[4-(2-hydroxyethyl)-1-piperazino]-6,7-dimethoxy-quinoline, m.p.176°-177° C.

x. 2-[4-(2-hydroxyethyl)-1-piperazino]-6,7-dimethoxy-quinoline nitratedihydrochloride, m.p. 223°-226° C.(decomp.).

y. 3-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline.

z. 3-[3-bis(2-hydroxyethyl)aminopropyl]amino-quinoline dinitrate, as anoil, N.M.R. --CH₂ ONO₂ triplet δ 4.62 p.p.m., --NH broad singlet δ 8.0p.p.m., I.R. --ONO₂ strong peaks 1280 cm⁻ ¹, 1640 cm⁻ ¹,

z-1. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-7-chloro-quinoline, m.p.105.5°-107.5° C.

z-2. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-7-chloro-dinitratetrihydrochloride form, 140°-142° C.(decomp.).

z-3. 4-[4-(2-hydroxyethyl)-1-piperazino]-7-chloro-quinoline, m.p.119°-121° C.

z-4. 4-[4-2-hydroxyethyl)-piperazino]-7-chloro-quinoline nitrate,dihydrochloride form, m.p. 150°-151° C.(decomp.).

z-5. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-6-methoxy-quinoline,dimaleate form, m.p. 144.5°-146° C.

z-6. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-6-methoxy-quinolinedinitrate, m.p. 80°-81° C.

z-7. 4-(5-hydroxypentyl)amino-7-methoxy-quinoline, m.p. 139°-140° C.

z-8. 4-(5-hydroxypentyl)amino-7-methoxy-quinoline nitrate, maleate form,m.p. 144.5°-146° C.

z-9. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-7-methoxyquinoline, m.p.103.5°-106°° C.

z-10. 4-[3-bis(2-hydroxyethyl)aminopropyl]amino-7-methoxy-quinolinedinitrate difumarate form, m.p. 88° C.

z-11. 4-(5-hydroxypentyl)amino-6-methoxy-quinoline.

z-12. 4-(5-hydroxypentyl)amino-6-methoxy-quinoline nitrate maleate, m.p.88°-90° C.

z-13. 4-(5-hydroxypentyl)amino-7-chloro-quinoline.

z-14. 4-(5-hydroxypentyl)amino-7-chloro-quinoline nitrate, hydrochlorideform, m.p. 126°-128° C.

z-15. 4-(2,3-dihydroxypropyl)amino-7-chloro quinoline.

z-16. 4-(2,3-dihydroxypropyl)amino-7-chloro quinoline dinitrate, maleateform, m.p. 137°-138° C. (decomp.).

z-17.4-{N-methyl-N-[3-bis(2-hydroxyethyl)aminopropyl]amino}-6,7-dimethoxy-quinolinedifumarate form, m.p. 94°-95.5° C.

z-18.4{N-methyl-N-[3-bis(2-hydroxyethyl)aminopropyl]amino}-6,7-dimethoxy-quinolinedinitrate difumarate form, as an oil, N.M.R. N--CH₃ singlet ˜δ 3.1p.p.m. --OCH₃ singlet˜δ 3.9 p.p.m., --CH₂ ONO₂ triplet˜δ 4.5 p.p.m.

z-19 4-{N-methyl-N-[3-bis(2-hydroxyethyl)aminopropyl]amino}quinoline.

z-20. 4-{N-methyl-N-]3-bis(2-hydroxyethyl)aminopropyl]amino}quinolinedinitrate difumarate form, m.p. 109°-110° C.

z-21. 4-(4-hydroxybutyl)amino-7-chloro-quinoline, m.p. 180° C.

z-22. 4-(4-hydroxybutyl)amino-7-chloro-quinoline nitrate, m.p. 142° C.

z-23. 4-(4-hydroxybutyl)amino-7-methoxy-quinoline, m.p. 128°-129° C.

z-24. 4-(4-hydroxybutyl)amino-7-methoxy-quinoline nitrate, m.p. 131° C.

z-25. 4-(4-hydroxybutyl)amino-8-methoxy-quinoline, m.p. 148°-150° C.

z-26. 4-(4-hydroxybutyl)amino-8-methoxy-quinoline nitrate hydratehydrochloride.

z-27. 4-(6-hydroxyhexyl)amino-7-methoxy-quinoline, m.p. 124.5°-125.5° C.

z-28. 4-(6-hydroxyhexyl)amino-7-methoxy-quinoline nitrate hydrochloride,m.p. 145.5°-150° C. (decomp.).

z-29. 4-(6-hydroxyhexyl)amino-7-chloro-quinoline hydrochloride, m.p.156°-157° C.

z-30. 4-(6-hydroxyhexyl)amino-7-chloro-quinoline nitrate hydrochloride,m.p. 145° C.

z-31. 4-[4-(2-hydroxyethyl)-1-piperazino]-6-methoxy-quinolinedihydrochloride, m.p. 255°-258° C.

z-32. 4-[4-(2-hydroxyethyl)-1-piperazino]-6-methoxy-quinoline nitratedihydrochloride, m.p. 160° C.

z-33. 4-[4-(2-hydroxyethyl)-1-piperazino]-7-methoxy-quinoline, m.p.122.5°--123.5° C.

z-34. 4-[4-(2-hydroxyethyl)-1-piperazino]-7-methoxy-quinoline nitrate,dihydronitrate form, m.p. 153° C.

z-35. 4-[4-(2-hydroxyethyl)-1-piperazino]-8-methoxy-quinoline, m.p.162°-163° C.

z-36. 4-[4-(2-hydroxyethyl)-1-piperazino]-8-methoxy-quinoline nitratedihydrochloride, m.p. 180° C. (decomp.).

z-37. 4-(6-hydroxyhexyl)amino-8-methoxy-quinoline.

z-38. 4-(6-hydroxyethyl)amino-8-methoxy-quinoline nitrate hydronitrate,m.p. 144°-147° C.

z-39. 4-(7-hydroxyheptyl)amino-7-chloroquinoline.

z-40. 4-(7-hydroxyheptyl)amino-7-chloroquinoline nitrate hydrochloride,m.p. 119.5°-121° C.

z-41. 4-(7-hydroxyheptyl)amino-7-methoxyquinoline.

z-42. 4-(7-hydroxyheptyl)amino-7-methoxyquinoline nitrate hydrochloride,m.p. 148°-148.5° C.

z-43. 4-(7-hydroxyheptyl)amino-8-methoxyquinoline.

z-44. 4-(7-hydroxyheptyl)amino-9-methoxyquinoline nitrate, hydronitrateform, m.p. 170°-173° C. (decomp.).

z-45. 4-(1,3-dihydroxypropyl)amino-6,7-dimethoxy-quinoline.

z-46. 4-(1,3-dihydroxypropyl)amino-6,7-dimethoxy- quinoline dinitratehydrochloride.

EXAMPLE 5 1-Methyl-4-(5-hydroxypentyl)amino-7-chloro-quinoline nitrateiodide. ##STR11##

A mixture of 3.0 g. of 4-(5-hydroxypentyl)amino-7-chloro-quinolinenitrate and 20 ml. of methyl iodide is refluxed for 20 minutes. To thecooled reaction mixture is added dry diethyl ether to completecrystallization and the solids are collected by filtration, washed twicewith diethyl ether and dried in a high vacuum to obtain1-methyl-4-(5-hydroxypentyl)amino-7-chloro-quinoline nitrate iodide,m.p. 184°-186° C.(decomp).

EXAMPLE 6

Following the procedure of Example 5 the following additional compoundsof the invention are prepared:

a. 1-methyl-4-(5-hydroxypentyl)amino-7-chloro-quinoline iodide,209°-211° C. (decomp.).

b. 1-methyl-4-(5-hydroxypentyl)amino-6-methoxy-quinoline nitrate iodide,m.p. 132°-133° C.

c. 1-methyl-4-(5-hydroxypentyl)amino-7-methoxy-quinoline nitrate iodide,m.p. 182°-183° C. (decomp.).

d. 1-methyl-4-(5-hydroxypentyl)amino-6-methoxy-quinoline iodide, m.p.210°-212° C. (decomp.).

e. 1-methyl-4-(5-hydroxypentyl)amino-8-methoxy-quinoline nitrate iodide,m.p. 49°-51° C.

f. 1-methyl-4-(5-hydroxypentyl)amino-8-methoxy-quinoline iodide, m.p.121°-122.5° C.

g. 1-methyl-4-(4-hydroxybutyl)amino-7-chloroquinoline iodide, m.p. 231°C.

h. 1-methyl-4-(4-hydroxybutyl)amino-7-chloroquinoline nitrate iodide,m.p. 160° C.

i. 1-methyl-4-(4-hydroxybutyl)amino-7-methoxyquinoline iodide.

j. 1-methyl-4-(4-hydroxybutyl)amino-7-methoxyquinoline nitrate iodide,m.p. 166° C.

k. 1-methyl-4-(4-hydroxybutyl)amino-8-methoxyquinoline iodide, m.p.127°-128.5° C.

l. 1-methyl-4-(4-hydroxybutyl)amino-8-methoxyquinoline nitrate iodide,m.p. 126°-128° C.

m. 1-methyl-4-(6-hydroxyhexyl)amino-7-chloroquinoline iodide, m.p.223°-224° C.

n. 1-methyl-4-(6-hydroxyhexyl)amino-7-chloroquinoline nitrate iodide,m.p. 170° C.

o. 1-methyl-4-(6-hydroxyhexyl)amino-7-methoxyquinoline iodide, m.p.209°-212° C.

p. 1-methyl-4-(6-hydroxyhexyl)amino-7-methoxyquinoline nitrate iodide,m.p. 162°-164° C. (decomp.).

q. 1-methyl-4-(6-hydroxyhexyl)amino-8-methoxyquinoline iodide, m.p.88°-91° C.

r. 1-methyl-4-(6-hydroxyhexyl)amino-8-methoxyquinoline nitrate iodide,m.p. 99°-100.5° C.

s. 1-methyl-4-(7-hydroxyheptyl)amino-7-chloroquinoline nitrate iodide,m.p. 135° C.

t. 1-methyl-4-(7-hydroxyheptyl)amino-7-methoxyquinoline nitrate iodide,m.p. 165° C. (decomp.).

u. 1-methyl-4-(7-hydroxyheptyl)amino-8-methoxyquinoline nitrate iodide,m.p. 83°-86° C.

v. 1-trifluoromethyl-4-(5-hydroxypentyl)amino-8-methoxyquinoline nitrateiodide.

What is claimed is:
 1. A compound of the formula: ##STR12## wherein R₂is from the group of:(a) --CH₂ (--CH₂)_(n) --OH ##STR13## (d) --CH₂(--CH₂)_(z) --N[CH₂ (--CH₂)_(y) --OH]₂ R₃ is from the group of:(e) --CH₂(--CH₂)_(n) --OH when R₂ is a) as above defined, (f) hydrogen, (g) loweralkyl of 1 to 4 carbon atoms, R_(a) ' is --(CH₂ --)_(x) CH₃ or --(CH₂--)_(y) OH, R_(a) ^(o) is hydrogen, --(CH₂ --)_(m) CH₃ or --(CH₂ --)_(y)OH, provided that one R_(a) ^(o) is other than hydrogen, that the sum ofn and m does not exceed 7 and that the sum of n and y does not exceed 8,or R₂ and R₃ together with the 4-amino nitrogen attached to quinolinering form ##STR14## n is 1 to 7, m is 0 to 4, x is 0 or 1, y is 1 to 4,z is 1 to 4, andeach of Y, Y', Y" and Y'" is hydrogen, halo of atomicweight of from 18 to 80, alkoxy of 1 to 3 carbon atoms, or alkyl of 1 to3 carbon atoms, or Y and Y' together form methylenedioxy, provided atleast 2 of Y, Y', Y" and Y'" are hydrogen and further provided that whenone of Y, Y', Y", Y'" is halo then the others are hydrogen, or apharmaceutically acceptable acid addition salt thereof.
 2. A compound ofclaim 1 in which R₃ is hydrogen.
 3. A compound of claim 2 in which R₂ is--CH₂ (--CH₂)_(n) --OH.
 4. A compound of claim 2 in which R₂ is --CH₂(--CH₂)_(z) --N[--CH₂ (--CH₂)_(y) --OH]₂.
 5. The compound of claim 4 inwhich Y', Y" and Y'" are hydrogen, Y is methoxy, z is 2 and y is
 1. 6.The compound of claim 4 in which Y" and Y'" are hydrogen, Y and Y' areeach methoxy, z is 2 and y is
 1. 7. The compound of claim 1 in which R₂is --CH₂ CHOHCH₂ OH, R₃ is hydrogen and each of Y, Y', Y" and Y'" ishydrogen.
 8. A compound of claim 1 in which R₂ and R₃ together with theamino nitrogen attached to the quinoline ring form: ##STR15##
 9. Thecompound of claim 8 in which z is 1, Y' is methoxy and Y, Y" and Y'" areeach hydrogen.
 10. The compound of claim 8 in which z is 1 and each ofY, Y', Y" and Y'" is hydrogen.
 11. A compound of the formula: ##STR16##wherein y is 1 to 4, z is 1 to 4, andeach of Y, Y', Y" and Y'" ishydrogen, halo of atomic weight of from 18 to 80, alkoxy of 1 to 3carbon atoms, or alkyl of 1 to 3 carbon atoms, or Y and Y' together formmethylenedioxy, provided that at least 2 of Y, Y', Y" and Y'" arehydrogen and further provided that when one of Y, Y', Y" and Y'" is halothen the others are hydrogen, or a pharmaceutically acceptable acidaddition salt thereof.
 12. The compound of claim 11 in which Y, Y' andY'" are hydrogen, Y" is methoxy, z is 2, y is 1.